Respiratory syncytial virus (RSV) is a major and highly contagious respiratory pathogen that most people are exposed to within the first year or two of life. It is the dominant cause of severe lower respiratory-tract disease (bronchiolitis and pneumonia) in infants and young children, leading to approximately 100,000 hospitalizations each year in the United States alone (HEILMAN 1990). There are two major antigenically distinct subgroups of RSV, A and B, which can circulate simultaneously and are responsible for predictable winter epidemics each year. In adults and older children, symptoms resemble the common cold and are normally mild and confined to the upper respiratory tract. However, in infants and young children, RSV infection often progresses to the lower respiratory tract, where it can lead to serious respiratory complications requiring hospitalization and, in rare cases, may even result in death. Infants with underlying cardiac or pulmonary disease, and some premature/low-birth-weight infants are at considerably higher risk of more severe disease and increased mortality from RSV infection, and are candidates for prophylactic intervention during the winter months. Although not well studied, immunosuppressed adult populations (the elderly, organ-transplant recipients) are also prone to life-threatening infections.

ABSTRACT We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (≤35 weeks’ gestation) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SB 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura ( n = 3) and thrombocytosis ( n = 1). No subject developed a detectable level of anti-SB 209763 antibody. Approximately 1 week after administration of the second dose of SB 209763 at 10 mg/kg, the mean plasma concentration ( n = 9) was 68.5 μg/ml. The terminal half-life ( T 1/2 ) determined by noncompartmental analysis ranged from 22 to 50 days. The population pharmacokinetics for SB 209763 following intramuscular administration was appropriately described by a one-compartment model with first-order input and elimination. Higher values for clearance and volume of distribution at steady state were observed for younger patients, with values decreasing to 0.143 (ml/h)/kg and 161 mL/kg, respectively, by a mean age of 298 days (∼10 months). The mean T 1/2 of SB 209763 for the study population was 32.5 days. No other factor (dose, weight, gender, race, premature birth, or bronchopulmonary dysplasia) was observed to alter the population pharmacokinetics of SB 209763 in this study of infants and young children. The mean neutralization titer on day 6 was 286, and the mean fusion inhibition titer was 36. At least 57% of subjects dosed at 1.25 to 10.0 mg of SB 209763 per kg of body weight who were seronegative at baseline experienced a fourfold or greater increase in fusion inhibition titer. Nine RSV infections were documented during the 16-week course of the study; the numbers of RSV infections were similar for the different regimens, including the placebo. The doses of SB 209763 studied may have been insufficient to confer protection against RSV lower respiratory tract disease; these results suggest that additional trials using higher doses of monoclonal antibody for immunoprophylaxis should be considered.

Objective: To evaluate the usefulness of 6 beta-hydroxycortisol as a screen for CYP3A induction in early-phase drug development.Methods: Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily (2) placebo once daily (3) 40 mg SB 216469 tn ice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day, All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24-hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6 beta-hydroxycortisol and 17-hydroxycorticosteroid concentrations.Results: Subjects in the rifampin group had a significant increase from predose value in the 24-hour urinary excretion of 6 beta-hydroxycortisol and the ratio of 6 beta-hydroxycortisol to 17-hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6 beta-hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio, The placebo and three active treatment groups did not show significant changes in either parameter.Conclusions: Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A.

Recent studies have suggested that intravenous infusion of fenoldopam, a selective dopamine-1 receptor agonist, elevates intraocular pressure (IOP) in man. This study evaluated the effect of intravenous fenoldopam on IOP, aqueous humor outflow facility and gonioscopy in 12 healthy human subjects. Three doses (0.2, 0.5 and 1.0 microg/kg/min) were infused for 120 minutes in a double masked, placebo controlled, four-way crossover design. IOP was measured every 20 minutes in the supine position and every 40 minutes while sitting during the drug and placebo infusions. Tonography and gonioscopy were performed at baseline and after 120 minutes of infusion. Compared to placebo, IOP increased by 3.5 mm Hg (32%) for the lowest dose, 5.8 mm Hg (46%) for the intermediate dose, and 6.9 mm Hg (55%) for the highest dose (p<0.05 for all three doses). IOP returned to baseline within 30 minutes of stopping the infusion. The outflow facility decreased from baseline by 26% after 120 minutes of infusion for all drug doses. In contrast, outflow facility increased from baseline by 11% during placebo infusion. Compared to placebo, the fenoldopam induced changes in outflow were statistically significant (p<0.05). There was no change in the gonioscopic appearance of the anterior chamber angle during the infusion. This study shows that systemic administration of a selective dopamine-1 receptor agonist causes a significant dose-dependent increase in IOP that can be explained in part by diminished outflow facility. These results support a role for the dopamine-1 receptor in the modulation of IOP in general and suggest modulation of aqueous humor outflow by dopaminergic receptors.

Potent CYP3A4 inhibitors such as ketoconazole can cause dangerous increases in plasma concentrations of the H-1 antagonist terfenadine. In light of recent reports that the selective serotonin reuptake inhibitor antidepressants may be weak CYP3A4 inhibitors, this study was designed to investigate the effects of paroxetine on the pharmacodynamic and pharmacokinetic profile of terfenadine. Twelve healthy male volunteers participated in a randomized open-label, two-period, steady-state crossover study. Terfenadine (60 mg twice daily for 8 days) was administered alone and with paroxetine at steady state (20 mg once daily for 15 days, with terfenadine on days 8 through 15). Extensive electrocardiogram monitoring was conducted throughout, and terfenadine and carboxyterfenadine pharmacokinetics were assessed at the end of each treatment period. One subject withdrew because of adverse experiences related to paroxetine, but the other 11 subjects completed the study uneventfully. On the final day of coadministration, the rate-corrected QT interval (QTc) was unaltered compared with terfenadine dosed alone; maximum QTc values (mean [SEM]) were 404 (4) and 405 (5) msec, respectively. Terfenadine pharmacokinetics were also unchanged; geometric mean steady-state area under the curve (AUC)tau values were 30.0 ng.hr/mL during coadministration compared with 30.8 ng.hr/mL when dosed alone (p > 0.05). The corresponding Cmax values were 3.68 and 3.64 ng/mL (p > 0.05). There was, however, a small (on average 17-20%), unexplained reduction in the steadystate Cmax and AUCtau of carboxyterfenadine during coadministration with paroxetine. In conclusion, paroxetine does not affect the pharmacokinetics or cardiovascular effects of terfenadine. The small reduction in carboxyterfenadine plasma concentrations is unlikely to be important clinically.

Intravenous fenoldopam, a selective dopamine‐1 receptor agonist, was compared with placebo in this randomized, double‐blind, two‐period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open‐angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 μg/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P <0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam‐associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine‐1 receptors play a role in the regulation of intraocular pressure.

Clinical Pharmacology & Therapeutics (1996) 59, 201–201; doi: 10.1038/sj.clpt.1996.302

BACKGROUND:Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users.METHODS:We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly.RESULTS:Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002).CONCLUSION:We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.

Single ascending doses of RSHZ19 (also known as SB 209763), a humanized monoclonal antibody (MAb) directed to the fusion protein of respiratory syncytial virus, were administered to healthy men to evaluate the safety, pharmacokinetics, antigenicity, and fusion inhibition (FI) activity of RSHZ19. Doses of RSHZ19 (0.025-10.0 mg/kg) or placebo were infused over 30 min, and subjects were followed for 10 weeks. Plasma concentrations of RSHZ19 and RSHZ19-specific antibodies were determined by ELISAs. FI titers were used to evaluate the ability of plasma to inhibit virus-induced fusion of VERO cells previously infected with RS Long strain virus. Twenty-six subjects, mean age 24, completed the study. RSHZ19 was safe and well tolerated, and no subject developed antibodies to RSHZ19 during follow-up. RSHZ19 had low plasma clearance and a half-life of approximately 23 days, similar to native IgG. Increases in FI titers relative to pretreatment levels were seen 24 h after MAb administration in all 4 subjects given 10 mg/kg and in 2 of 4 given 5 mg/kg.

Clinical Pharmacology & Therapeutics (1996) 59, 144–144; doi: 10.1038/sj.clpt.1996.76

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side‐effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21–43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period‐balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE 2 , 6‐keto‐PGF 1α , PGF 2α , thromboxane [TX] B 2 ) and platelet function (collagen‐induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE 2 and PGF 2α , but 6‐keto‐PGF1 α and TXB 2 excretion were unchanged. IND treatment did not result in a significant change in PGE 2 excretion but did significantly reduce urinary 6‐keto‐PGF 1α and TXB 2 excretion rates. Reduced excretion of PGF 2α was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE 2 excretion while significantly reducing 6‐keto‐PGF 1α excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF 2α excretion and between the NAB and SUL regimens for PGE 2 , PGF 2α , 6‐keto‐PGF α1 (on day 1 only) and TXB 2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE 2 and 6‐keto‐PGF 1α , suggests that NAB possesses renal sparing properties.

Bohn, Rhonda L. M.P.H.; Glynn, Robert J. Sc.D.; Gurwitz, Jerry H. M.D.; Everitt, Daniel E. M.D.; Gilden, Daniel M.S.; Avorn, Jerry M.D.

We conducted a case-control study to measure the risk of pulmonary side effects following the use of topical glaucoma medications, particularly the beta blockers, and to identify patients at highest risk for such side effects. Patients over age 55 who were active users of the New Jersey Medicaid system during the years 1981-1989 composed the study population. Two case groups were identified: (a) 21,096 patients who began new use of bronchodilator medications and (b) 3,382 patients who were users of a xanthine bronchodilator or inhaled steroid whose regimen was intensified through addition of another medication (generally a sympathomimetic). Controls were Medicaid enrollees with documented use of the Medicaid system. Use of glaucoma medications was measured in the 45 days preceding occurrence of the outcome for cases, and during a comparable period for controls. We found no consistent association between ongoing glaucoma therapy and new use of a bronchodilator; a definitive null result was obtained for timolol (odds ratio = 0.95; 95% CI = 0.84-1.09). However, nonselective topical beta blockers remained commonly used among patients already on a bronchodilator regimen. Timolol users were 47% more likely to require addition of another class of bronchodilator than were patients using no glaucoma therapy (odds ratio = 1.47; 95% CI 1.04-2.09; p = 0.03). No increase in risk was found for other glaucoma drugs. These findings suggest that patients with bronchospasm requiring xanthines or inhaled steroids who are prescribed topical timolol for glaucoma may be at significantly increased risk of pulmonary symptom exacerbation requiring additional bronchodilator therapy. No risk was found for the initiation of bronchodilators in previously untreated patients.

ABSTRACT:The records of 22 cases of family‐mediated abuse and neglect of elderly persons were retrospectively reviewed by the physician and nurse responsible for their care using a modification of the OARS Multidimensional Functional Assessment form. Cases were divided into three categories: Category I cases (n = 4) involved extremely impaired elders who received extensive care from the individuals responsible for the abuse or neglect. Category II cases (n = 9) involved impaired elders who received inadequate or intermittent care. Category III cases (n = 9) involved independent elders whose only care needs resulted from threats or violence from relatives. Among the statistically significant differences found between these categories were the age of the abuser, the manifestations of abuse or neglect, the interventions offered, the durations of abuse, and the outcomes of the cases. The results suggest that these three categories represent different subgroups of abused and neglected elderly persons, all with different implications for identification, intervention, and outcome.